Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000806558 | SCV000946562 | pathogenic | Charcot-Marie-Tooth disease type 2 | 2023-10-16 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 582 of the LMNA protein (p.Arg582Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with lipodystrophy (PMID: 22700598, 30177912, 33502018). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 651240). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LMNA protein function. This variant disrupts the p.Arg582 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10739751, 11231979, 20130076, 28641778). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Mayo Clinic Laboratories, |
RCV001509065 | SCV001715576 | uncertain significance | not provided | 2020-10-13 | criteria provided, single submitter | clinical testing | |
| Mendelics | RCV002249518 | SCV002517570 | pathogenic | Dilated cardiomyopathy 1A | 2022-05-04 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002397643 | SCV002712137 | likely pathogenic | Cardiovascular phenotype | 2021-05-06 | criteria provided, single submitter | clinical testing | The p.R582C variant (also known as c.1744C>T), located in coding exon 11 of the LMNA gene, results from a C to T substitution at nucleotide position 1744. The arginine at codon 582 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in several individuals with familial partial lipodystrophy (FPLD) in both the heterozygous and homozygous state (Montenegro RM et al. Front Endocrinol (Lausanne), 2018 Aug;9:458; Mory PB et al. Eur J Endocrinol, 2012 Sep;167:423-31). A likely pathogenic alteration, p.R582H, has been described at the same codon. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| All of Us Research Program, |
RCV004001686 | SCV004819669 | uncertain significance | Primary dilated cardiomyopathy | 2023-03-09 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with cysteine at codon 582 of the LMNA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with a complex lipodystrophy phenotype including arrhythmia (PMID: 22700598). It has also been reported in a family with lipodystrophy (PMID: 30177912). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |